In both Europe and the United States an estimated 5 to 6 million people sustain bone fractures each year due to trauma, sports- or activity-related injuries or osteoporosis. Most of these injuries may be treated with manual reduction and external fixation (e.g. a cast). However approximately 20 to 25% of fractures require hospitalization, usually with open surgical procedures.
With respect to fractures, bone fragments do not have to separate for the injury to be classified as a fracture. In some cases the periosteum holds the bone fragments in their original anatomical position. In other cases, the fracture causes the limb to bend, tearing the periosteum or even the surrounding skin and muscle tissue. In still other cases, as is often the case with high-velocity missile injuries or serious accidents, large portions of bone are fragmented or even removed from its original location. The primary goals of fracture treatments are sound union and the restoration of bone function without an outcome of deformity. Obtaining these goals quickly is an increasingly important concern due to disability issues and cost-containment. In a significant part of the patient population both goals, i.e. sound unions and fast restoration of bone function, are at risk due to the patient's age and/or general health condition, and/or the type and/or location of fracture. In particular, in case of osteoporotic patients, the risk of non-unions and increased healing times is high. As a disease of the skeleton, osteoporosis is characterised by low bone mass and the structural deterioration of bone tissue leading to increased bone fragility, increased healing times and the occurrence of non-union.
Bone grafts and bone graft substitutes are widely used in many orthopaedic procedures to treat problems associated with bone loss, delayed union and non-union fractures or as an implant fixation material. In case of severe and complicated fractures, bone graft and bone graft substitutes are used to fill the bone voids and assist the fracture union process after the fracture is stabilized with hardware. Bone grafting materials may be autogenic, allogenic, xenogenic, demineralised bone matrix (DBM), of synthetic origin or mixtures thereof. Bone grafting materials can be classified into materials with osteoconductive, osteoinductive and osteogenic properties. Osteoconductive materials do not create bone; rather they simulate the migration of nearby living bone cells into the material. Osteoinductive materials stimulate the patient's own system to generate bone tissue. Osteogenic materials directly create bone tissue either by stimulating the proliferation of osteoblasts or promoting mesenchymal stem cells to generate bone tissue. Some materials exhibit more than one of the described properties.
Bone autografts are usually harvested from the iliac crest. In spite their advantage of being biocompatible, safe, of a vascularized composition and exhibiting osteoinductive properties, the disadvantages are major. Autografts require a second operation which may lead to postoperative complications which include blood-loss, infections and pain. Autografts are costly due to longer hospital stays and operation time. The supply of autografts per patient is limited, and the post operative pain after harvesting of autogenic material is often higher than the bone fracture itself In spite of the disadvantages, autograft is considered the “gold standard” in terms of bone grafting materials. Laurencin, et al. Expert Review Medical Devices 1:49-57 (2006). Allografts are minimally osteoinductive, there is only limited supply, and they pose on the patient the risk of infections due to host pathogens.
Synthetic bone graft materials are developed as an “off-the-shelf” alternative to autogenic bone grafting material. Synthetic bone graft substitutes include ceramic materials and self-setting polymers such as hydroxyapatite and polymethylmethacrylate, collagen, tricalciumphosphate, calcium sulfates and calcium-phosphates, that mimic properties of human bone. However, these materials show poor handling properties and a lack of osteoinductive properties.
In recent years efforts have been made to develop bone graft substitutes which show osteoinductive properties as a true “off-the-shelf alternative” to autografts. DBM is one example of an osteoinductive bone graft substitute. However DBM as an allogenic material faces the same drawbacks like allogenic bone. Other examples are Stryker Corp.'s OP-1® (recombinantly produced bone morphogenic protein 7 (BMP 7) in a collagen matrix) or Medtronic Sofamor Danek's INFUSE® (bone graft substitute material using recombinantly produced BMP2 from collagen sponges). Apart from the expensive and lengthy production process of the BMPs, the proteins in both products are delivered from a collagen matrix in high concentrations. However, collagen matrices from bovine origin carry all the risks of xenogenic materials and show poor handling properties in the surgical procedure, e.g. they are not moldable to closely fit to the shape of the injury site, and the high concentration of BMPs delivered to the body can lead in some of the patients to calcification of organs or to bone formation in other parts of the body.
The N-terminal 34 amino acid domain of the human parathyroid hormone (PTH1-34) has been reported to be biologically equivalent to the full length hormone. Parathyroid hormone 1-34 and its mode of action have been first reported in U.S. Pat. No. 4,086,196 to Tregear. PTH1-34 is known to be a fully active truncated version of parathyroid hormone which does not have disulfide bonds or significant tertiary structure. It contains a moderate secondary structure, including several alpha helices. Many clinical studies have been carried out using systemically administered parathyroid hormone to increase the overall bone mass in patients with osteoporosis, with the majority requiring daily injections of parathyroid hormone or PTH1-34 alone, or in combination with other actives, for many months. More details about PTH and PTH1-34 are described in WO 03/052091, the content thereof being incorporated herein by reference. Other truncated versions of parathyroid hormone with biological activity include parathyroid hormone 1-25 (PTH1-25), 1-31 (PTH1-31) and 1-38 (PTH1-38).
While much work has been done studying the systemic effects of PTH, the local administration of PTH has barely been explored. WO 03/052091 describes matrices for local administration of PTH. Specifically, WO 03/052091 describes parathyroid hormone as being covalently attached to synthetic and natural matrices, in particular fibrin or polyethyleneglycol matrices, for local administration and release at the site of need in a controlled fashion.
However, WO 03/052091 does not describe methods for the healing bone fractures, in particular severe bone fractures, like repair of fractures at risk of becoming delayed unions or non-unions.
It is therefore, an object of the present invention to provide a matrix which is suitable for the local repair of bone fractures.
It is further an object of the present invention to provide a method for repairing bone fractures.